Velia Fowler, Ph.D.

Research Interests

The Fowler laboratory studies cellular architecture: how cells spatially organize themselves and their interior compartments to achieve intricate geometries, mechanical strength, and physiological functions. The basis of cellular architecture is the cytoskeleton, a collection of specialized and dynamic “building blocks” that act as a cell’s scaffolding. Our investigations into the cytoskeleton focus on structural elements known as actin and myosin filaments, with an emphasis on how these nanoscale components generate microscale cellular architecture and macroscale tissue and organ function. We are interested in how the cytoskeleton provides mechanical stability and produces contractile forces that shape membrane curvature and confer mechanical resilience during cell differentiation, morphogenesis and aging. Our approaches include biochemistry, biophysics, super-resolution fluorescence microscopy, mouse genetics and physiology, and analysis of human cells from patients with congenital diseases.

Publication Covers

Read about dynamic actin filaments and cell architecture:
https://www.scripps.edu/newsandviews/i_20011210/fowler1.html
 

Current Projects

1. Red Blood Cell Shape

The biconcave disk shape and deformability of mammalian red blood cells (RBCs) rely upon the membrane skeleton, a viscoelastic network of short actin filaments interconnected by long spectrin tetramers in a periodic lattice. Unlike many other cell types, RBCs can be easily isolated in large quantities and contain no transcellular or cytoplasmic cytoskeleton, allowing the membrane skeleton to be studied in isolation from other populations of actin or myosin. Since periodic spectrin-actin networks are present in other cells, such as neurons and epithelial cells, the RBC membrane provides a unique paradigm for exploration of fundamental principles in membrane biology. Recently, our lab discovered that non-muscle myosin IIA (NMIIA) motors interact with the spectrin-actin network to maintain RBC biconcave shape and deformability. We are studying nanoscale lattice structure and NMIIA assembly using super-resolution fluorescence microscopy; membrane curvature and cell shape using 3D confocal microscopy; cell deformability using biomechanical assays; and physiology using hematological assays. By examining RBCs from human patients and transgenic mice with mutations in NMIIA or membrane skeleton components, we can reveal the molecular and structural basis of RBC shape, deformability, and physiology. We also collaborate with computational cell biologists to model how NMIIA forces exerted on the nanoscale network structure determine microscale membrane curvature and biconcave shapes.

Read more about the spectrin-actin lattice here: http://www.bloodjournal.org/content/116/14/2406
Read more about myosin and RBC shape here: http://www.pnas.org/content/115/19/4813.long
Read an article in “The Scientist” about Actomyosin and RBC shape:  https://www.the-scientist.com/the-literature/how-red-blood-cells-get-their-dimples-64680

2.  Red Blood Cell Formation

Biogenesis of mammalian RBCs (erythropoiesis) is a highly orchestrated process of terminal differentiation in which regulated gene expression directs a series of cell divisions coupled to dramatic changes in cell and nuclear morphology, culminating in cell cycle exit and nuclear expulsion (enucleation). While enucleation has been described morphologically for decades, the molecular mechanisms that drive the process remain unclear. We study erythroblast enucleation in hematopoietic organs (bone marrow, spleen, and fetal liver) from transgenic mice and in human hematopoietic stem cells with actin cytoskeleton mutations. We identify critical components by genetics, proteomics and biochemistry, analyze 3D cell shape and cytoskeleton architecture using confocal and super-resolution fluorescence microscopy, observe dynamics of fluorescent-tagged cellular components using time-lapse microscopy of living erythroblasts, and determine enucleation forces using computational modeling. These studies will elucidate molecular mechanisms of human congenital anemias due to defects in erythropoiesis and enucleation and provide strategies for optimizing RBC production in vitro for future applications in transfusion medicine.

Read more about the actin cytoskeleton and enucleation here: http://www.bloodjournal.org/content/123/5/601

3.  Eye Lens Function

The lens functions to fine focus light onto the retina to produce a clear image. For proper functioning, the lens not only has to be clear but also must be an appropriate size, shape, and mechanical stiffness. Age-associated conditions of the lens include cataracts (lens cloudiness) and presbyopia (difficulty to focus on close objects). Despite decades of study, the exact mechanisms underpinning these aging conditions remain unclear. Using transgenic mice and other mammalian model systems combined with genomic, proteomic, and biochemical approaches, we aim to identify the actin cytoskeleton components that determine lens growth, cell sizes and shapes, and their microstructural mechanical responses. We utilize electron microscopy and high-and super-resolution fluorescence confocal microscopy to evaluate the complex 3-dimensional shapes and structures of lens cells. Additionally, by utilizing specialized equipment we mechanically compress or stretch lenses to evaluate biomechanical properties, and collaborate with engineers and computational biologists to model forces within the lens. This will enable us to understand how the actin cytoskeleton establishes lens size, shape, and biomechanical properties, and how cytoskeleton dysfunction may contribute to cataracts and/or presbyopia. 

Read more about lens fiber cell hexagonal packing here: http://jcb.rupress.org/content/186/6/768.3
Listen to an interview about lens cell shape and the cytoskeleton.
http://jcb.rupress.org/sites/default/files/biobytes/biobytes_sep_21_2009.mp3
 

Research Group

  • Meet Velia Fowler: http://www.asbmb.org/asbmbtoday/201401/VeliaFowler/
  • Justin Parreno, Postdoctoral Fellow and Lab Manager (Ph.D., University of Toronto, Canada). Lens mechanobiology.
  • Kasturi Pal, Postdoctoral Fellow (Ph.D., University of California Riverside, CA).  Actomyosin regulation in red blood cells.
  • Arit Ghosh, Postdoctoral Fellow (Ph.D., University of California Riverside, CA). Actin cytoskeleton regulation of erythropoiesis.
  • Graduate Positions Open

Selected Publications

Last 5 years:

  • Parreno, J., Fowler, V.M. Multifunctional Roles of Tropomodulin-3 in Regulating Actin Dynamics. Biophys Rev.  Invited Review.
  • Zhao, Y., Wilmarth, P.A., Cheng, C., Limi, S., Fowler, V.M., Zheng, D., David, L.L., Cvekl, A. (2018)  Proteome-transcriptiome analysis and proteome remodeling in mouse lens epithelium and fibers.  Exp. Eye Res., in press.
  • Cheng, C., Nowak, K.J., Amadeo, M.B., Biswas, S.K., Lo, W.K., Fowler, V.M. (2018). Tropomyosin 3.5 protects F-actin networks required for tissue biomechanical properties. J. Cell Sci. In Press.
  • Omotade, O.F., Rui, Y., Lei, W., Yu, K., Hartzell, H.C., Fowler, V.M., Zheng, J.Q. (2018). Tropomodulin Isoform-Specific Regulation of Dendrite Development and Synapse Formation. J Neurosci. pii: 3325-17. doi: 10.1523/J NEUROSCI.3325-17.2018. PubMed.
  • Smith, A., Nowak, R.B., Fowler, V.M. (2018). High-Resolution Fluorescence Microscope Imaging of Erythroblast Structure. Methods Molecular Biology. 1698:205-228. doi: 10.1007/978-1-4939-7428-3_12. PubMed.
  • Smith, A.S., Nowak, R.B., Zhou, S., Giannetto, M., Gokhin, D.S., Papoin, J., Ghiran, I.C., Blanc, L., Wan, J., and V.M. Fowler. (2018). Myosin IIA interacts with the spectrin-actin membrane skeleton to control red blood cell membrane curvature and deformability. PNAS,. 115(19):E4377-E4385. PubMed. Recommended by F1000Prime. Commentary in PNAS:  http://www.pnas.org/content/115/19/4813.long.
  • Parreno, J., Cheng, C., Nowak, R.B., Fowler, V.M. (2018). The effects of mechanical strain on mouse eye lens capsule and cellular microstructure. Mol Biol Cell. 29(16):1963-1974. PubMed.
  • Fowler, V.M., and R. Dominguez (2017)  Tropomodulins and Leiomodins: Actin Pointed End Caps and Nucleators in Muscles. Biophys. J. 112:1-19. PubMed.
  • Cheng, C., Fowler, V.M., and X. Gong. (2017) EphA2 and ephrin-A5 are not a receptor-ligand pair in the ocular lens.  Exp. Eye Res. 162:9-17. PubMed.
  • Sui, Z., Gokhin, D.S., Nowak, R.B., Guo, X., An, X., and V.M. Fowler. (2017)  Stabilization of F-actin by tropomyosin isoforms regulates the morphology and mechanical behavior of red blood cells. Mol. Biol. Cell. 28:2531-2542. PubMed.
  • Nowak, R.B., Papoin, J., Gokhin, D.S., Casu, C., Rivella, S., Lipton, J.M., Blanc, L., Fowler, V.M. (2017) Tropomodulin 1 controls erythroblast enucleation via regulation of F-actin in the enucleosome. Blood. 130(9):1144-1155. PubMed.
  • Wu, T., Mu, Y., Bogomolovas, J., Fang, X., Veevers, J., Nowak, R.B., Pappas, C.T., Gregorio, C.C., Evans, S.M., Fowler, V.M., Chen, J. (2017) HSPB7 is indispensable for heart development by modulating actin filament assembly. Proc. Natl. Acad. Sci. U S A. 114(45):11956-11961. PubMed.
  • Cheng, C., Gokhin, D.S., Nowak, R.B., and V.M. Fowler.  (2016) Sequential application of glass coverslips to assess the compressive stiffness of the mouse lens.  J. of Visualized Experiments, 2016 May 3;(111). PubMed.
  • Cheng, C., Nowak, R.B., Biswas, S.K., Lo, W.K., FitzGerald, P.G., and V.M. Fowler. (2016) Tropomodulin 1 regulation of actin is required for the formation of large paddle protrusions between mature lens fiber cells. Invest. Ophthalmol.Vis. Sci. 57:4084-4099. PubMed.
  • Gokhin, D.S. and V.M. Fowler. (2016) Software-based measurement of thin filament lengths: an open-source GUI for Distributed Deconvolution analysis of fluorescence images. J. of Microscopy. 265 (1):11-20. PubMed.
  • Cheng, C., Nowak, R., and V.M. Fowler. (2016)  The lens actin filament cytoskeleton: diverse structures for complex functions.  Exp. Eye Res. S0014-4835(16)30035-5. PubMed.
  • Gokhin, D.S., and V.M. Fowler.  (2016)  Feisty filaments: actin dynamics in the red blood cell membrane skeleton. Curr. Opin. Hematology. 23(3):206-14. PubMed.
  • Yuen, M., S.A. Sandaradura, J.J. Dowling, et al.  (2015)  Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy.  J. Clin. Invest. 125(11):456-7. PubMed.
  • Gokhin, D.S., R.B. Nowak, J.A. Khoory, A. de la Piedra, I.C. Ghiran, and V.M. Fowler.  (2015)  Dynamic actin filaments control the mechanical behavior of the human red blood cell membrane.  Mol. Biol. Cell. 26(9):1699-710.  PMID: 25717184; A highlights from MBoC selection. PubMed.
  • Cheng, C., R.B. Nowak, J.Gao, X. Sun, S.K. Biswas, W.-K. Lo, R.T. Mathias, and V.M. Fowler.  (2015)  Lens ion homeostasis relies on the assembly of large connexin 46 gap junction plaques on the broad sides of differentiating fiber cells. Amer. J. Physiol. Cell Physiol.  308: C835-C847. PubMed.
  • Sui, Z., Nowak, R.B., Sanada, C., Halene, S., Krause, D.S., and V.M. Fowler. (2015)  Regulation of actin polymerization by tropomodulin3 controls megakaryocyte actin organization and platelet biogenesis.  Blood. 126(4):520-530. With accompanying cover image. PubMed.
  • Liang, R., Camprecios, G., Kou, Y., McGrath, K., Nowak, R., Catherman, S., Bigarella, C., Rimmele P, Zhang, X., Gnanapragasam, M.N., Bieker, J., Papatsenko, D., Ma'ayan, A., Bresnick, E., Fowler, V.M., Palis, J., Ghaffari, S. (2015)  A systems approach identifies essential FOXO3 functions at key steps of terminal erythropoiesis.  PLoS Genetics, 11(10):e1005526. PubMed.
  • Fischer, R.S. (Editor) and V.M. Fowler (Co-Editor).  (2015)  Thematic mini-review series: The state of the cytoskeleton in 2015. J. Biol. Chem. 290(28):17133-17136. doi: 10.1074/jbc.R115.663716.  With accompanying cover image. PubMed.
  • Gokhin, D.S., Ochala, J., Domenighetti, A.A., and V.M. Fowler. (2015)  Tropomodulin1 directly controls thin filament length in both wild-type and tropomodulin4-deficient skeletal muscle. Development, 142(24):4351-62. PubMed.
  • Sui, Z., R.B. Nowak, A. Bacconi, N.E. Kim, H. Liu, J. Li, A. Wickrema, X.L. An and V.M. Fowler.  (2014)  Tropomodulin3-null mice are embryonic lethal with anemia due to impaired erythroid terminal differentiation in the fetal liver. Blood 123:758-767. With accompanying cover image.  Highlighted in Blood: http://www.bloodjournal.org/content/123/5/601. PubMed.
     

Professional Experience

  • 1980-1982 Jane Coffin Childs Postdoctoral Fellow NIADDK, NIH, and Dept Cell Biology and Anatomy, Johns Hopkins University School of Medicine
  • 1983-1984 Research Associate, Dept Cell Biology and Anatomy, Johns Hopkins University School of Medicine
  • 1984-1987 Assistant Professor, Dept Anatomy and Cell Biology, Harvard Medical School
  • 1987-1993 Assistant Professor, Depts Molecular and Cell Biology, The Scripps Research Institute (TSRI)
  • 1993-2000 Associate Professor, Dept Cell Biology, TSRI
  • 2000-2015 Professor, Dept Cell and Molecular Biology, TSRI
  • 2013-pres. Associate Dean for Graduate Studies, TSRI
  • 2014-2015 Chair (Acting), Department of Cell and Molecular Biology, TSRI
  • 2016-2018 Professor, Department of Molecular Medicine, TSRI.
     

Awards & Professional Activities

  • 1975-1978 National Science Foundation Predoctoral Fellowship Award
  • 1980-1982 Jane Coffin Childs Foundation Postdoctoral Fellowship Award
  • 1983-1984 NIH New Investigator Research Grant Award
  • 1990-1995 American Heart Association Established Investigator Award
  • 2001-2003 Chair, Cell and Developmental Function 6 (CDF6) Study Section for Postdoctoral Fellowships and AREA grants, NIH
  • 2003 Chair, “Motile and Contractile Systems” Gordon Research Conference, Colby-Sawyer College, NH
  • 2009-2010 Erythrocyte and Leukocyte Biology (ELB) NIH Study Section
  • 2010-2013 Molecular and Cellular Hematology (MCH) NIH Study Section
  • 2010 ASCB Program Committee 2011 Annual Meeting
  • 2011 Chair, “Red Cells” Gordon Research Conference, Proctor Academy, Andover, NH
  • 2011 Lens and Cataract Program Planning Panel, National Eye Institute, NIH
  • 2011-2017 Associate Program Director & Imaging Core Director, San Diego Skeletal Muscle Research Center for NIAMS/NIH P30 Core
  • 2013-2015 Scientific Advisory Board, French National Grant, “Le Globule Rouge”, Laboratoires d’Excellence” (GR-Ex), Paris, France
  • 2014 Program Organizer Lens Section, International Society for Eye Research XX1st Biennial Conference. 2005- Editorial Board, Cytoskeleton
  • 2012-pres. Editorial Board Member, Journal of Biological Chemistry
  • 2013-pres. Associate Editor, Journal of Biological Chemistry
  • 2017 Chair, ARVO Annual Meeting Program Committee, Lens Section (LE).

Incoming Chair

Phone: (302) 831-4296

Fax: (302) 831-2281

Email: vfowler@udel.edu

Office: 118 Wolf Hall

Lab: 341 Wolf Hall

Address:
Department of Biological Sciences
105 The Grn,
118 Wolf Hall
Newark, DE 19716

Education

  • B.A. - Oberlin College, Oberlin, OH
  • Ph.D. - Harvard University, Cambridge, MA
  • National Science Foundation Predoctoral Fellow
  • Postdoctoral - Jane Coffin Childs Postdoctoral
  • Fellow, The National Institutes of Health and Johns Hopkins University School of Medicine